Updated on 2026/03/14

写真a

 
ISHIHARA Tomohiko
 
Organization
Brain Research Institute Clinical Neuroscience Branch Department of Neurology Associate Professor
Title
Associate Professor
External link

Degree

  • 博士 （医学） ( 2011.3   新潟大学 )

Research Interests

  • 神経変性疾患

  • RNA代謝

  • 筋萎縮性側索硬化症

  • 脊髄小脳変性症

Research Areas

  • Life Science / Neuroscience-general

Research History

  • Niigata University   Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute   Associate Professor

    2025.5

  • Niigata University   Brain Research Institute   Specially Appointed Associate Professor

    2023.4 - 2025.4

  • Niigata University   University Medical and Dental Hospital Neurology   Lecturer

    2019.8 - 2023.3

  • Niigata University   Brain Research Institute Center for Bioresources   Assistant Professor

    2013.4 - 2019.7

  • Niigata University   Brain Research Institute Clinical Neuroscience Branch   Assistant Professor

    2011.5 - 2013.3

Professional Memberships

 

Papers

  • ABCC6 pathogenic variants are associated with hemorrhagic phenotypes in Japanese patients with severe cerebral small vessel disease

    Sho Kitahara, Shoichiro Ando, Masahiro Uemura, Yuya Hatano, Hiroaki Nozaki, Daisuke Hirozawa, Emi Nomura, Kohei Okubo, Asami Munekane, Takumi Tashiro, Kanako Asai, Minako Yamaoka, Tomone Taneda, Yutaka Honma, Hajime Kondo, Ryo Itabashi, Akira Iwanaga, Hiroyuki Murota, Hitoshi Aizawa, Tomohiko Ishihara, Osamu Onodera

    Scientific Reports   2026.1

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s41598-025-33934-3

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  • Specific Contribution of the Cerebellar Inferior Posterior Lobe to Motor Learning in Degenerative Cerebellar Ataxia

    Kyota Bando, Takeru Honda, Kinya Ishikawa, Shinichi Shirai, Ichiro Yabe, Tomohiko Ishihara, Osamu Onodera, Yuichi Higashiyama, Fumiaki Tanaka, Yoshiyuki Kishimoto, Masahisa Katsuno, Takahiro Shimizu, Ritsuko Hanajima, Takumi Kanata, Yuji Takahashi, Hidehiro MizusawaMD

    The Cerebellum   24 ( 5 )   2025.7

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1007/s12311-025-01887-y

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    Other Link： https://link.springer.com/article/10.1007/s12311-025-01887-y/fulltext.html

  • “Chocolate Chip Sign” on Susceptibility-Weighted Imaging

    Shoichiro Ando, Rie Saito, Sho Kitahara, Masahiro Uemura, Yuya Hatano, Masaki Watanabe, Taisuke Kato, Yosuke Ito, Atchayaram Nalini, Tomohiko Ishihara, Shigeo Murayama, Hironaka Igarashi, Akiyoshi Kakita, Osamu Onodera

    Neurology Genetics   11 ( 2 )   2025.4

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    Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

    DOI： 10.1212/nxg.0000000000200237

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  • Redefining the Pathogenic CAG Repeat Units Threshold in CACNA1A for Spinocerebellar Ataxia Type 6 Reviewed

    Yuya Hatano, Tomohiko Ishihara, Sachiko Hirokawa, Hidetoshi Date, Yuji Takahashi, Hidehiro Mizusawa, Osamu Onodera

    Neurology Genetics   11 ( 2 )   2025.4

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1212/NXG.0000000000200245

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  • The analysis of schizophrenia-like psychosis in dentatorubral-pallidoluysian atrophy. International journal

    Ichiko Ikegami, Yuka Mitsuhashi Koike, Hideki Hayashi, Sachiko Hirokawa, Shoichiro Ando, Tomohiko Ishihara, Osamu Onodera

    Frontiers in neurology   16   1564856 - 1564856   2025

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disorder caused by expanded CAG repeats in the ATN1 gene, characterized by cerebellar ataxia, seizures, tremors, and myoclonus. Although approximately 10% of patients with DRPLA reportedly develop schizophrenia-like psychosis (SLP), the distinct association between the clinical course of DRPLA and SLP remains unclear. This study aimed to elucidate the clinical features of SLP in patients with DRPLA. METHODS: We reviewed 22 cases of pathologically or genetically confirmed DRPLA with SLP, including 21 from the literature and one from our institution. Patient data, including clinical features, treatment information, and disease course, were extracted and analyzed. RESULTS: The age of onset was categorized as juvenile (n = 6), early adult (n = 8), and late adult (n = 8). Initially, 10 patients presented with motor symptoms, with six exhibiting psychiatric symptoms and six with both motor and psychiatric symptoms simultaneously. Furthermore, three patients were initially diagnosed with schizophrenia, while four experienced progressive worsening of psychiatric symptoms. The number of CAG repeats ranged from 57 to 76 (mean, 66.0) in the 10 patients with a genetic diagnosis. Summarily, 12 patients received psychotropic medications, with nine showing improvement in delusions and hallucinations. CONCLUSION: SLP can manifest across all DRPLA forms (juvenile-, early adult-, and late adult-onset) and may precede or follow motor symptoms. The clinical course and efficacy of psychotropic medications in patients with DRPLA and SLP suggest a shared pathogenesis between DRPLA and schizophrenia.

    DOI： 10.3389/fneur.2025.1564856

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  • SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan

    Tomohiko Ishihara, Akihide Koyama, Naoki Atsuta, Mari Tada, Saori Toyoda, Kenta Kashiwagi, Sachiko Hirokawa, Yuya Hatano, Akio Yokoseki, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Ryuji Kaji, Mitsuya Morita, Asako Tamura, Osamu Kano, Masashi Aoki, Satoshi Kuwabara, Akiyoshi Kakita, Gen Sobue, Osamu Onodera

    BMC Medical Genomics   17 ( 1 )   2024.11

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1186/s12920-024-02026-y

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    Other Link： https://link.springer.com/article/10.1186/s12920-024-02026-y/fulltext.html

  • L-arginine in patients with spinocerebellar ataxia type 6: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

    Tomohiko Ishihara, Masayoshi Tada, Yoshitomi Kanemitsu, Yuji Takahashi, Kinya Ishikawa, Kensuke Ikenaka, Makito Hirano, Takanori Yokota, Eiko N. Minakawa, Katsuhisa Saito, Yoshitaka Nagai, Osamu Onodera

    eClinicalMedicine   102952 - 102952   2024.11

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.eclinm.2024.102952

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  • Reliability study for the Japanese version of the Columbia Muscle Cramp Scale in amyotrophic lateral sclerosis

    Masahiro Sawada, Takehisa Hirayama, Masaru Yanagihashi, Koji Fukushima, Yuishin Izumi, Tameto Naoi, Mitsuya Morita, Hitoshi Warita, Masashi Aoki, Yohei Iguchi, Masahisa Katsuno, Nobuhiro Ogawa, Makoto Urusitani, Tomohiko Ishihara, Osamu Onodera, Yoshitaka Murakami, Hiroshi Mitsumoto, Osamu Kano

    Neurology and Clinical Neuroscience   2024

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/ncn3.12838

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  • TDP-43は運動回路の変性を誘導するために異なって伝播する(TDP-43 differentially propagates to induce degeneration in the motor circuit)

    坪口 晋太朗, 中村 由香, 石原 智彦, 加藤 泰介, 佐藤 時春, 小山 哲秀, 森 秀樹, 小池 佑佳, 小野寺 理, 上野 将紀

    Dementia Japan   37 ( 4 )   680 - 680   2023.10

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    Language：English   Publisher：(一社)日本認知症学会  

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  • SCA6の浸透性に関する研究(Study of penetrance of SCA6)

    Hatano Yuya, Ishihara Tomohiko, Hirokawa Sachiko, Onodera Osamu

    臨床神経学   63 ( Suppl. )   S335 - S335   2023.9

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    Language：English   Publisher：(一社)日本神経学会  

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  • 【神経変性疾患の眼球運動異常】脊髄小脳変性症の眼球運動の特徴や異常

    小出 眞悟, 石原 智彦, 小野寺 理

    神経眼科   40 ( 3 )   222 - 228   2023.9

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    Language：Japanese   Publisher：日本神経眼科学会  

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  • TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models. International journal

    Shintaro Tsuboguchi, Yuka Nakamura, Tomohiko Ishihara, Taisuke Kato, Tokiharu Sato, Akihide Koyama, Hideki Mori, Yuka Koike, Osamu Onodera, Masaki Ueno

    Acta neuropathologica   2023.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

    DOI： 10.1007/s00401-023-02615-8

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  • Inappropriate interpretation of non-pathogenic HTRA1 variant as pathogenic. International journal

    Masahiro Uemura, Sho Kitahara, Taisuke Kato, Hiroaki Nozaki, Shoichiro Ando, Tomohiko Ishihara, Osamu Onodera

    Annals of clinical and translational neurology   10 ( 7 )   1261 - 1262   2023.7

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  • Accuracy of a machine learning method based on structural and locational information from AlphaFold2 for predicting the pathogenicity of TARDBP and FUS gene variants in ALS

    Yuya Hatano, Tomohiko Ishihara, Osamu Onodera

    BMC Bioinformatics   24 ( 1 )   2023.5

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Abstract

    Background

    In the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some ALS causative genes, the pathogenic variants are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.

    Methods

    We analyzed variants of 12 ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, SOD1, VCP, SQSTM1, ANG, UBQLN2, DCTN1, and CCNF) and classified them as pathogenic or neutral. For each gene, the features of the variants, consisting of their positions in the 3D structure predicted by AlphaFold2, pLDDT score, and BLOSUM62 were trained into a random forest and evaluated by the stratified fivefold cross validation method. We compared how accurately MOVA predicted mutant pathogenicity with other in silico prediction methods and evaluated the prediction accuracy at TARDBP and FUS hotspots. We also examined which of the MOVA features had the greatest impact on pathogenicity discrimination.

    Results

    MOVA yielded useful results (AUC ≥ 0.70) for TARDBP, FUS, SOD1, VCP, and UBQLN2 of 12 ALS causative genes. In addition, when comparing the prediction accuracy with other in silico prediction methods, MOVA obtained the best results among those compared for TARDBP, VCP, UBQLN2, and CCNF. MOVA demonstrated superior predictive accuracy for the pathogenicity of mutations at hotspots of TARDBP and FUS. Moreover, higher accuracy was achieved by combining MOVA with REVEL or CADD. Among the features of MOVA, the x, y, and z coordinates performed the best and were highly correlated with MOVA.

    Conclusions

    MOVA is useful for predicting the virulence of rare variants in which they are concentrated at specific structural sites, and for use in combination with other prediction methods.

    DOI： 10.1186/s12859-023-05338-5

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    Other Link： https://link.springer.com/article/10.1186/s12859-023-05338-5/fulltext.html

  • Machine Learning Approach for the Prediction of Age-Specific Probability of SCA3 and DRPLA by Survival Curve Analysis

    Yuya Hatano, Tomohiko Ishihara, Sachiko Hirokawa, Osamu Onodera

    Neurology Genetics   9 ( 3 )   e200075 - e200075   2023.5

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    Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

    Background and Objectives

    As the number of repeats in the expansion increases, polyglutamine diseases tend to show at a younger age. From this relationship, attempts have been made to predict age at onset by parametric survival analysis. However, a method for a more accurate prediction has been desirable. In this study, we examined 2 methods for survival analysis using machine learning and 6 conventional methods for parametric survival analysis of spinocerebellar ataxia (SCA)3 and dentatorubral-pallidoluysian atrophy (DRPLA).

    Methods

    We compared the performance of 2 machine learning methods of survival analysis (random survival forest [RSF] and DeepSurv) and 6 methods of parametric survival analysis (Weibull, exponential, Gaussian, logistic, loglogistic, and log Gaussian). Training and evaluation were performed using the leave-one-out cross-validation method, and evaluation criteria included root mean squared error (RMSE), mean absolute error (MAE), and the integrated Brier score. The latter was used as the primary end point, and the survival analysis model yielding the best result was used to predict the asymptomatic probability.

    Results

    Among the models examined, the RSF and DeepSurv machine learning methods had a higher prediction accuracy than the parametric methods of survival analysis. For both SCA3 and DRPLA, RSF had a higher accuracy than DeepSurv for the assessment of RMSE (SCA3: 7.37, DRPLA: 10.78), MAE (SCA3: 5.52, DRPLA: 8.17), and the integrated Brier score (SCA3: 0.05, DRPLA: 0.077). Using RSF, we determined the age-specific probability distribution of age at onset based on CAG repeat size and current age.

    Discussion

    In this study, we have demonstrated the superiority of machine learning methods for predicting age at onset of SCA3 and DRPLA using survival analysis. Such accurate prediction of onset will be useful for genetic counseling of carriers and for devising methods to verify the effects of interventions for unaffected individuals.

    DOI： 10.1212/nxg.0000000000200075

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  • High frequency of<i>HTRA1</i>AND<i>ABCC6</i>mutations in Japanese patients with adult-onset cerebral small vessel disease

    Masahiro Uemura, Yuya Hatano, Hiroaki Nozaki, Shoichiro Ando, Hajime Kondo, Akira Hanazono, Akira Iwanaga, Hiroyuki Murota, Yosuke Osakada, Masato Osaki, Masato Kanazawa, Mitsuyasu Kanai, Yoko Shibata, Reiko Saika, Tadashi Miyatake, Hitoshi Aizawa, Takeshi Ikeuchi, Hidekazu Tomimoto, Ikuko Mizuta, Toshiki Mizuno, Tomohiko Ishihara, Osamu Onodera

    Journal of Neurology, Neurosurgery &amp; Psychiatry   jnnp - 2022   2022.10

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    Publishing type：Research paper (scientific journal)   Publisher：BMJ  

    Background

    This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.

    Methods

    This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or &gt;55 years and with a positive family history (group 2). After conducting conventional genetic tests forNOTCH3andHTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups.

    Results

    Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134).

    Conclusions

    More than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

    DOI： 10.1136/jnnp-2022-329917

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  • The CAG repeat length of CACNA1A in both alleles affects the age of onset of SCA6(タイトル和訳中)

    Hatano Yuya, Ishihara Tomohiko, Hirokawa Sachiko, Onodera Osamu

    臨床神経学   62 ( Suppl. )   S364 - S364   2022.10

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  • 日本人小脳失調症患者におけるRFC1のACAGG反復モチーフの拡大(Expansion of the ACAGG repeat motif in RFC1 in Japanese patients with cerebellar ataxia)

    Koide Shingo, Ishihara Tomohiko, Hirokawa Sachiko, Sakakibara Satoko, Aiba Ikuko, Onodera Osamu

    臨床神経学   62 ( Suppl. )   S364 - S364   2022.10

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  • 全身性疾患に伴う脊椎病変 頸椎除圧術後の上肢型筋萎縮側索硬化症の臨床経過

    五十嵐 哲也, 渡辺 慶, 大橋 正幸, 川島 寛之, 三瓶 一弘, 五十嵐 修一, 黒羽 泰子, 小池 亮子, 石原 智彦, 大津 裕, 小野寺 理

    東北整形災害外科学会雑誌   65 ( 1 )   167 - 168   2022.6

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    Language：Japanese   Publisher：東北整形災害外科学会  

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  • 全身性疾患に伴う脊椎病変 頸椎除圧術後の上肢型筋萎縮側索硬化症の臨床経過

    五十嵐 哲也, 渡辺 慶, 大橋 正幸, 川島 寛之, 三瓶 一弘, 五十嵐 修一, 黒羽 泰子, 小池 亮子, 石原 智彦, 大津 裕, 小野寺 理

    東北整形災害外科学会雑誌   65 ( 1 )   167 - 168   2022.6

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  • Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. International journal

    Ryosuke Oki, Yuishin Izumi, Koji Fujita, Ryosuke Miyamoto, Hiroyuki Nodera, Yasutaka Sato, Satoshi Sakaguchi, Hiroshi Nokihara, Kazuaki Kanai, Taiji Tsunemi, Nobutaka Hattori, Yuki Hatanaka, Masahiro Sonoo, Naoki Atsuta, Gen Sobue, Toshio Shimizu, Kazumoto Shibuya, Ken Ikeda, Osamu Kano, Kazuto Nishinaka, Yasuhiro Kojima, Masaya Oda, Kiyonobu Komai, Hitoshi Kikuchi, Nobuo Kohara, Makoto Urushitani, Yoshiaki Nakayama, Hidefumi Ito, Makiko Nagai, Kazutoshi Nishiyama, Daisuke Kuzume, Shun Shimohama, Takayoshi Shimohata, Koji Abe, Tomohiko Ishihara, Osamu Onodera, Sagiri Isose, Nobuyuki Araki, Mitsuya Morita, Kazuyuki Noda, Tatsushi Toda, Hirofumi Maruyama, Hirokazu Furuya, Satoshi Teramukai, Tatsuo Kagimura, Kensuke Noma, Hiroaki Yanagawa, Satoshi Kuwabara, Ryuji Kaji

    JAMA neurology   79 ( 6 )   575 - 583   2022.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

    DOI： 10.1001/jamaneurol.2022.0901

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  • Mutation screening of the DNAJC7 gene in Japanese patients with sporadic amyotrophic lateral sclerosis. International journal

    Genki Tohnai, Ryoichi Nakamura, Naoki Atsuta, Masahiro Nakatochi, Naoki Hayashi, Daisuke Ito, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Akira Taniguchi, Kazuaki Kanai, Mitsuya Morita, Osamu Kano, Satoshi Kuwabara, Masaya Oda, Koji Abe, Masashi Aoki, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Tomohiko Ishihara, Akihiro Kawata, Takanori Yokota, Kazuko Hasegawa, Isao Nagano, Ichiro Yabe, Fumiaki Tanaka, Satoshi Kuru, Nobutaka Hattori, Kenji Nakashima, Ryuji Kaji, Gen Sobue

    Neurobiology of aging   113   131 - 136   2022.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    DNAJC7 has recently been identified as an amyotrophic lateral sclerosis (ALS) gene via large-scale exome analysis, and its involvement in ALS is still unclear in various populations. This study aimed to determine the frequencies and characteristics of the DNAJC7 variants in a Japanese ALS cohort. A total of 807 unrelated Japanese patients with sporadic ALS were screened via exome analysis. In total, we detected six rare missense variants and one splice-site variant of the DNAJC7 gene, which are not reported in the Japanese public database. Furthermore, the missense variants are located around the TPR domain, which is important for the function of DNAJC7. The total frequency of the DNAJC7 variants in Japanese ALS patients was estimated at 0.87%. Collectively, these results suggest that variants of DNAJC7 are rare cause of Japanese patients with sporadic ALS.

    DOI： 10.1016/j.neurobiolaging.2021.12.002

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  • Endogenous human retrovirus-K is not increased in the affected tissues of Japanese ALS patients International journal

    Tomohiko Ishihara, Akihide Koyama, Yuya Hatano, Ryoko Takeuchi, Yuka Koike, Taisuke Kato, Mari Tada, Akiyoshi Kakita, Osamu Onodera

    Neuroscience Research   178   78 - 82   2022.5

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

    Activation of human endogenous retrovirus-K (HERV-K) is one of the proposed risk factors for amyotrophic lateral sclerosis (ALS). The HERV-K envelope protein has been reported to show neurotoxicity, and development of therapy with reverse transcriptase inhibitors is being investigated. On the other hand, some reports have failed to show HERV-K activation in ALS. In this study, we analyzed the expression of HERV-K mRNA in the motor cortex and spinal cord of 15 Japanese patients with sporadic ALS and 19 controls using reverse transcriptase droplet digital PCR. This revealed no significant increase of HERV-K expression in ALS-affected tissues, suggesting that the association between ALS and HERV-K remains questionable.

    DOI： 10.1016/j.neures.2022.01.009

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  • [ATTRv amyloidosis with early improvement demonstrated by the 6-minute walk test following Patisiran therapy: a case report].

    Shinya Oginezawa, Tomohiko Ishihara, Yohei Iwafuchi, Yuya Hatano, Ken Kashimura, Osamu Onodera

    Rinsho shinkeigaku = Clinical neurology   62 ( 5 )   375 - 379   2022.4

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    We report the case of a 65-year-old man who gradually developed numbness in both hands, lower limb muscle weakness and atrophy, and orthostatic hypotension over two and a half years. These symptoms indicated hereditary ATTR amyloidosis (ATTRv amyloidosis), and the final diagnosis was established through proof of TTR gene mutation (V30M). We initiated patisiran therapy, and a continuous 6-minute walking test performed 3 weeks from the start of therapy demonstrated improvement in the walking distance. This is a single case report showing the improvement in the motor and sensory function on administration of patisiran monotherapy from an early stage.

    DOI： 10.5692/clinicalneurol.cn-001693

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  • 加齢と関連したDNA脱メチル化がTDP-43量の自己調節機構を障害する

    小池 佑佳, 須貝 章弘, 原 範和, 伊藤 絢子, 横関 明男, 石原 智彦, 山岸 拓磨, 坪口 晋太朗, 他田 真理, 池内 健, 柿田 明美, 小野寺 理

    Dementia Japan   35 ( 4 )   610 - 610   2021.10

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  • パチシラン単独投与で早期より運動機能が改善したATTRアミロイドーシスの1例

    荻根沢 真也, 石原 智彦, 岩淵 洋平, 畠野 雄也, 柏村 健, 小野寺 理

    神経治療学   38 ( 6 )   S293 - S293   2021.10

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  • 当科での成人脊髄性筋萎縮症の診断・治療例

    石原 智彦, 今野 卓哉, 徳武 孝允, 井上 佳奈, 原 賢寿, 小野寺 理

    臨床神経学   61 ( Suppl. )   S322 - S322   2021.9

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  • Correction to: A novel splicing variant of ANXA11 in a patient with amyotrophic lateral sclerosis: histologic and biochemical features. International journal

    Makoto Sainouchi, Yuya Hatano, Mari Tada, Tomohiko Ishihara, Shoichiro Ando, Taisuke Kato, Jun Tokunaga, Gaku Ito, Hiroaki Miyahara, Yasuko Toyoshima, Akio Yokoseki, Tetsutaro Ozawa, Kohei Akazawa, Osamu Onodera, Akiyoshi Kakita

    Acta neuropathologica communications   9 ( 1 )   115 - 115   2021.6

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  • A novel splicing variant of ANXA11 in a patient with amyotrophic lateral sclerosis: histologic and biochemical features. International journal

    Makoto Sainouchi, Yuya Hatano, Mari Tada, Tomohiko Ishihara, Shoichiro Ando, Taisuke Kato, Jun Tokunaga, Gaku Ito, Hiroaki Miyahara, Yasuko Toyoshima, Akio Yokoseki, Tetsutaro Ozawa, Kohei Akazawa, Osamu Onodera, Akiyoshi Kakita

    Acta neuropathologica communications   9 ( 1 )   106 - 106   2021.6

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  • Hemiplegic-type ALS: clinicopathological features of two autopsied patients. International journal

    Makoto Sainouchi, Hidetomo Tanaka, Hiroshi Shimizu, Takuya Mashima, Takao Fukushima, Yuya Hatano, Tomohiko Ishihara, Kunihiko Makino, Osamu Onodera, Akiyoshi Kakita

    Journal of neurology, neurosurgery, and psychiatry   92 ( 9 )   1014 - 1016   2021.4

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  • 頸椎除圧術後の上肢型筋萎縮索硬化症の臨床経過

    五十嵐 哲也, 渡辺 慶, 大橋 正幸, 川島 寛之, 三瓶 一弘, 五十嵐 修一, 黒羽 泰子, 小池 亮子, 石原 智彦, 大津 裕, 小野寺 理

    日本整形外科学会雑誌   95 ( 2 )   S112 - S112   2021.3

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  • 頸椎除圧術後の上肢型筋萎縮索硬化症の臨床経過

    五十嵐 哲也, 渡辺 慶, 大橋 正幸, 川島 寛之, 三瓶 一弘, 五十嵐 修一, 黒羽 泰子, 小池 亮子, 石原 智彦, 大津 裕, 小野寺 理

    日本整形外科学会雑誌   95 ( 2 )   S112 - S112   2021.3

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  • Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex

    Yuka Koike, Akihiro Sugai, Norikazu Hara, Junko Ito, Akio Yokoseki, Tomohiko Ishihara, Takuma Yamagishi, Shintaro Tsuboguchi, Mari Tada, Takeshi Ikeuchi, Akiyoshi Kakita, Osamu Onodera

    2021.1

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    <title>Abstract</title>In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43) forms aggregates in the motor cortex of the aging brain. This aggregate formation may be triggered by the increase in TDP-43 levels with aging. However, the amount of TDP-43 is autoregulated by the alternative splicing of the <italic>TARDBP</italic> 3’UTR, and its relationship with aging remains unresolved. Since DNA methylation is altered during aging, we hypothesized that 3’UTR methylation is also altered in the aging motor cortex, disrupting this autoregulatory system and increasing TDP-43 levels. We found that DNA demethylation in the autoregulatory region of TDP-43 reduced alternative splicing and increased TDP-43 expression. Furthermore, in the human motor cortex, we found that this region was demethylated with age and that the expression of TDP-43 increased. The dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and system selectivity in ALS.

    DOI： 10.1101/2021.01.13.426599

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  • 基底核を主体とするメトロニダゾール脳症を呈した36歳女性例

    岩渕 洋平, 石原 智彦, 今野 卓哉, 徳武 孝允, 小野寺 理

    臨床神経学   61 ( 1 )   62 - 62   2021.1

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  • 筋萎縮性側索硬化症の確定診断までの時間に与える、初診科、発症部位の検討

    大津 裕, 小池 佑佳, 石原 智彦, 小野寺 理

    臨床神経学   60 ( Suppl. )   S380 - S380   2020.11

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  • 筋萎縮性側索硬化症の確定診断までの時間に与える、初診科、発症部位の検討

    大津 裕, 小池 佑佳, 石原 智彦, 小野寺 理

    臨床神経学   60 ( Suppl. )   S380 - S380   2020.11

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  • 日本におけるSOD1遺伝子変異陽性筋萎縮性側索硬化症患者の臨床的特徴

    中村 亮一, 熱田 直樹, 藤内 玄規, 林 直毅, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 阿部 康二, 石原 智彦, 小野寺 理, 梶 龍兒, 祖父江 元

    臨床神経学   60 ( Suppl. )   S381 - S381   2020.11

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  • ALS剖検例に関するテキストマイニングとエキソーム分析を用いたALSの新規候補遺伝子の探索(Search for new candidate genes for ALS by textmining and exome analysis of autopsy cases)

    Hatano Yuya, Ishihara Tomohiko, Yokoseki Akio, Tada Mari, Kakita Akiyoshi, Okuda Shujiro, Onodera Osamu

    臨床神経学   60 ( Suppl. )   S324 - S324   2020.11

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  • 散発性ALSの137症例における剖検物のエキソーム分析(Exome analysis in 137 autopsied sporadic ALS cases)

    Ishihara Tomohiko, Hatano Yuya, Yokoseki Akio, Tada Mari, Nakajima Takashi, Koike Ryoko, Kakita Akiyoshi, Onodera Osamu

    臨床神経学   60 ( Suppl. )   S309 - S309   2020.11

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  • FTLD/ALSモデルマウスにおけるTDP-43の皮質内と皮質脊髄内での増殖(Intracortical and corticospinal spreading of TDP-43 in mouse FTLD/ALS models)

    坪口 晋太朗, 中村 由香, 石原 智彦, 加藤 泰介, 小山 哲秀, 佐藤 時春, 吉田 富, 上野 将紀, 小野寺 理

    Dementia Japan   34 ( 4 )   524 - 524   2020.10

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  • 本邦の孤発性ALSにおけるAPOE2の認知症への影響の検討

    畠野 雄也, 石原 智彦, 他田 真理, 柿田 明美, 小野寺 理

    Dementia Japan   34 ( 4 )   521 - 521   2020.10

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  • Intracortical and corticospinal spreading of TDP-43 in mouse FTLD/ALS models(和訳中)

    坪口 晋太朗, 中村 由香, 石原 智彦, 加藤 泰介, 小山 哲秀, 佐藤 時春, 吉田 富, 上野 将紀, 小野寺 理

    Dementia Japan   34 ( 4 )   524 - 524   2020.10

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  • A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. International journal

    Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

    Communications biology   3 ( 1 )   526 - 526   2020.9

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    Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

    DOI： 10.1038/s42003-020-01251-2

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  • 頸椎除圧術後の筋萎縮側索硬化症の臨床経過

    五十嵐 哲也, 大橋 正幸, 田仕 英希, 渋谷 洋平, 関本 浩之, 石原 智彦, 大津 裕, 小野寺 理, 渡辺 慶

    東日本整形災害外科学会雑誌   32 ( 3 )   344 - 344   2020.8

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  • [Molecular mechanism of amyotrophic lateral sclerosis (ALS) from the viewpoint of the formation and degeneration of transactive response DNA-binding protein 43 kDa (TDP-43) inclusions]. Reviewed

    Sou Kasahara, Tomohiko Ishihara, Yuka Koike, Akihiro Sugai, Osamu Onodera

    Rinsho shinkeigaku = Clinical neurology   60 ( 2 )   109 - 116   2020.2

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    Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.

    DOI： 10.5692/clinicalneurol.cn-001362

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  • TAF15が主要に蓄積したFET病理を伴う筋萎縮性側索硬化症 剖検例の臨床病理学的特徴(Amsotrophic lateral sclerosis with TAF15-predominant FET pathology: clinicopathologic features of an autopsied patient)

    Cui Bo, Tada Mari, Hatano Yuya, Takeshima Akari, Ishihara Tomohiko, Sugai Akihiro, Tokutake Takayoshi, Kanazawa Masato, Onodera Osamu, Kakita Akiyoshi

    新潟医学会雑誌   133 ( 11-12 )   391 - 391   2019.12

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  • [Molecular Pathogenesis of Amyotrophic Lateral Sclerosis]. Reviewed

    Shintaro Tsuboguchi, Tomohiko Ishihara, Akihiro Sugai, Akio Yokoseki, Osamu Onodera

    Brain and nerve = Shinkei kenkyu no shinpo   71 ( 11 )   1183 - 1189   2019.11

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    The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.

    DOI： 10.11477/mf.1416201428

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  • Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions. Reviewed International journal

    Fumiaki Mori, Mari Tada, Tomoya Kon, Yasuo Miki, Kunikazu Tanji, Hidekachi Kurotaki, Masahiko Tomiyama, Tomohiko Ishihara, Osamu Onodera, Akiyoshi Kakita, Koichi Wakabayashi

    Acta neuropathologica communications   7 ( 1 )   165 - 165   2019.10

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    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. AIM: The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. MATERIAL AND METHODS: Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). RESULTS: Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. CONCLUSION: The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

    DOI： 10.1186/s40478-019-0824-1

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  • Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation. Reviewed International journal

    Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

    Neurobiology of disease   130   104534 - 104534   2019.10

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

    DOI： 10.1016/j.nbd.2019.104534

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  • 環軸椎後方固定術11年後に脳梗塞を繰り返した46歳男性例

    柴田 健太郎, 坂田 佑輔, 佐治 越爾, 石原 智彦, 小野寺 理, 平野 徹

    臨床神経学   59 ( 7 )   465 - 465   2019.7

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  • A new Japanese amyotrophic lateral sclerosis family with TARDBP (TDP-43) mutation Reviewed

    Tomohiko Ishihara

    Neurology and Clinical Neuroscience   2019.3

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    DOI： 10.1111/ncn3.12250

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  • A patient clinically diagnosed as multiple system atrophy harboring LRRK2 p.G2019S Reviewed

    Tomohiko Ishihara

    Clinical Parkinsonism & Related Disorders   1   100 - 101   2019

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    DOI： 10.1016/j.prdoa.2019.11.002

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  • The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial Reviewed International journal

    Tomohiko Ishihara

    JMIR Research Protocols   7 ( 12 )   e12046   2018.12

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    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12046.

    DOI： 10.2196/12046

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  • 脊髄動静脈瘻症例における水頭症と脳脊髄液Froin徴候

    滑川 将気, 中島 章博, 石原 智彦, 中村 公彦, 他田 正義, 小野寺 理

    臨床神経学   58 ( Suppl. )   S338 - S338   2018.12

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  • MSA-Pと鑑別を要したPARK8の75歳女性例

    林 秀樹, 石原 智彦, 斎藤 奈つみ, 安藤 昭一朗, 小野寺 理

    臨床神経学   58 ( 12 )   779 - 779   2018.12

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  • ALS診断におけるAwaji基準の有用性に関する、当科剖検例での後方視的検討

    茂木 崇秀, 石原 智彦, 竹島 明, 他田 真理, 他田 正義, 柿田 明美, 小野寺 理

    臨床神経学   58 ( Suppl. )   S265 - S265   2018.12

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  • 常染色体劣性脊髄小脳失調症の家系におけるC12orf4の新規変異と臨床的特徴

    長谷川 有香, 石原 智彦, 笠原 壮, 黒羽 泰子, 高橋 哲哉, 松原 奈絵, 小野寺 理, 小池 亮子

    臨床神経学   58 ( Suppl. )   S265 - S265   2018.12

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  • 臨床経過および画像所見よりMSA-Pとの鑑別を要したPARK8の一例

    石原 智彦, 林 秀樹, 齋藤 奈つみ, 安藤 昭一朗, 小野寺 理

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   12回   100 - 100   2018.7

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  • Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease Reviewed

    Natsumi Saito, Tomohiko Ishihara, Kensaku Kasuga, Mana Nishida, Takanobu Ishiguro, Hiroaki Nozaki, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa

    Prion   12 ( 2 )   147 - 149   2018.3

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    DOI： 10.1080/19336896.2018.1436926

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  • 血液透析療法下で、脳出血発症後に脳浮腫が急速進行した58歳女性例

    大津 裕, 金山 武史, 二宮 格, 石原 智彦, 保坂 聖子, 忰田 亮平, 成田 一衛, 小野寺 理

    臨床神経学   58 ( 1 )   55 - 55   2018.1

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  • Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data. Reviewed International journal

    Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

    Frontiers in neuroscience   12 ( FEB )   28 - 28   2018

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    DOI： 10.3389/fnins.2018.00028

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  • 有痛性筋痙攣に対して免疫グロブリン静注療法が有効であった筋萎縮性側索硬化症の1例

    茂木 崇秀, 石原 智彦, 他田 正義, 河内 泉, 下畑 享良, 小野寺 理

    神経治療学   34 ( 6 )   S199 - S199   2017.11

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  • The SMN gene copy number states in Japanese ALS patients

    Ishihara T, Toyoda S, Koyama A, Tada M, Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O

    JOURNAL OF THE NEUROLOGICAL SCIENCES   381   211-211   2017.10

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    DOI： 10.1016/j.jns.2017.08.604

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  • TDP-43 G357S変異を伴った家族性筋萎縮性側索硬化症の70歳男性例

    茂木 崇秀, 石原 智彦, 横関 明男, 他田 正義, 下畑 享良, 小野寺 理

    臨床神経学   57 ( 4 )   192 - 192   2017.4

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  • PRES: Posterior reversible encephalopathy syndrome

    Okamoto, A.K., Motohashi, K., Fujiwara, H., Ishihara, T., Ninomiya, I., Onodera, O., Fujii, Y.

    Brain and Nerve   69 ( 2 )   129 - 141   2017.2

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  • A case of central pontine and extrapontine myelinolysis after surgery for a pituitary tumor Reviewed

    Takanobu Ishiguro, Tomohiko Ishihara, Yuya Hatano, Takahiro Abe, Takayoshi Shimohata, Masatoyo Nishizawa

    Clinical Neurology   57 ( 1 )   21 - 25   2017

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    DOI： 10.5692/clinicalneurol.cn-000956

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  • SMN遺伝子欠失は日本における下位運動ニューロン疾患の発症リスクと関連する(SMN gene deletion is associated with developing risk of lower motor neuron disease in Japan)

    豊田 佐織, 石原 智彦, 小山 哲秀, 西澤 正豊, 小野寺 理

    臨床神経学   56 ( Suppl. )   S230 - S230   2016.12

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  • 脊髄小脳変性症に対するバレニクリン酒石酸塩の治療効果の検討

    他田 正義, 徳永 純, 徳武 孝允, 石原 智彦, 野崎 洋明, 関根 有美, 堅田 慎一, 横関 明男, 小野寺 理, 西澤 正豊

    臨床神経学   56 ( Suppl. )   S488 - S488   2016.12

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  • Performance of a real-time PCR–based approach and droplet digital PCR in detecting human parechovirus type 3 RNA Reviewed

    Yuta Aizawa, Akihide Koyama, Tomohiko Ishihara, Osamu Onodera, Akihiko Saitoh

    Journal of Clinical Virology   84   27 - 31   2016.11

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    DOI： 10.1016/j.jcv.2016.09.009

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  • Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. Reviewed International journal

    Akihide Koyama, Akihiro Sugai, Taisuke Kato, Tomohiko Ishihara, Atsushi Shiga, Yasuko Toyoshima, Misaki Koyama, Takuya Konno, Sachiko Hirokawa, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    Nucleic acids research   44 ( 12 )   5820 - 36   2016.7

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    DOI： 10.1093/nar/gkw499

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  • A senile case of late-onset Pompe’s disease Reviewed

    Hiroki Takano, Tomohiko Ishihara, Motomichi Kosuga, Torayuki Okuyama

    Internal Medicine   55 ( 18 )   2723 - 2725   2016

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    DOI： 10.2169/internalmedicine.55.6803

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  • 脊髄硬膜欠損を認めた脳表ヘモジデリン沈着症の73歳女性例

    清野 あずさ, 石黒 敬信, 石原 智彦, 矢島 直樹, 下畑 享良, 西澤 正豊

    臨床神経学   55 ( 4 )   288 - 288   2015.4

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  • Conformational disease and rna disease theory in the context of neurodegenerative diseases

    Ishihara Tomohiko, Onodera Osamu

    Neurodegenerative Disorders as Systemic Diseases   3 - 22   2015.1

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    DOI： 10.1007/978-4-431-54541-5_1

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  • Clinical course and serial brain MRI findings in a patient with Lissauer form of general paresis Reviewed

    Tomohiko Ishihara, Ayako Ishihara, Tetutaro Ozawa, Kazuhiro Sanpei, Takayoshi Shimohata, Masatoyo Nishizawa

    Clinical Neurology   55 ( 4 )   238 - 242   2015

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    DOI： 10.5692/clinicalneurol.55.238

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  • Varicella-zoster virus encephalitis localized to the bilateral medial temporal lobes Reviewed

    Ryuji Yajima, Kota Utsumi, Tomohiko Ishihara, Masato Kanazawa, Kouichirou Okamoto, Izumi Kawachi, Masatoyo Nishizawa

    Neurology: Neuroimmunology and NeuroInflammation   2 ( 4 )   2015

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    DOI： 10.1212/NXI.0000000000000108

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  • ALSでのStasimonヒトホモログmRNAのスプライシング異常の検討

    石原 智彦, 志賀 篤, 小山 哲秀, 柿田 明美, 西澤 正豊, 高橋 均, 小野寺 理

    臨床神経学   54 ( Suppl. )   S99 - S99   2014.12

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  • ALS関連TARDBP遺伝子変異は自身の選択的スプライシングに影響をおよぼすか?

    今野 卓哉, 小山 哲秀, 逸見 文昭, 小山 美咲, 須貝 章弘, 加藤 泰介, 石原 智彦, 西澤 正豊, 小野寺 理

    臨床神経学   54 ( Suppl. )   S200 - S200   2014.12

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  • 核内TDP-43減少は細胞質内TDP-43 mRNA増加をもたらす

    須貝 章弘, 小山 哲秀, 加藤 泰介, 今野 卓哉, 石原 智彦, 西澤 正豊, 小野寺 理

    臨床神経学   54 ( Suppl. )   S62 - S62   2014.12

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  • Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases Reviewed

    Osamu Onodera, Tomohiko Ishihara, Atsushi Shiga, Yuko Ariizumi, Akio Yokoseki, Masatoyo Nishizawa

    Neuropathology   34 ( 1 )   99 - 107   2014.2

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    DOI： 10.1111/neup.12070

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  • Aberration of the spliceosome in amyotrophic lateral sclerosis Reviewed

    Tomohiko Ishihara, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa

    Clinical Neurology   54 ( 12 )   1155 - 1157   2014

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    DOI： 10.5692/clinicalneurol.54.1155

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  • 筋萎縮性側索硬化症の脊髄前角細胞におけるCajal小体数の減少

    横関 明男, 譚 春鳳, 石原 智彦, 志賀 篤, 小山 哲秀, 佐藤 達哉, 高橋 均, 西澤 正豊, 小野寺 理

    臨床神経学   53 ( 12 )   1568 - 1568   2013.12

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  • ALS患者神経組織におけるU12 snRNAの減少とスプライシング異常

    石原 智彦, 志賀 篤, 有泉 優子, 横関 明男, 譚 春鳳, 柿田 明美, 西澤 正豊, 高橋 均, 小野寺 理

    臨床神経学   53 ( 12 )   1496 - 1496   2013.12

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  • Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. Reviewed International journal

    Tomohiko Ishihara, Yuko Ariizumi, Atsushi Shiga, Taisuke Kato, Chun-Feng Tan, Tatsuya Sato, Yukari Miki, Mariko Yokoo, Takeshi Fujino, Akihide Koyama, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    Human molecular genetics   22 ( 20 )   4136 - 47   2013.10

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    DOI： 10.1093/hmg/ddt262

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  • Conflict of intentions associated with leukodystrophy: A case report Reviewed

    Teduka, T., Shimohata, T., Ishihara, T., Otsuki, M., Odano, I., Nishizawa, M.

    Clinical Neurology   53 ( 2 )   114 - 118   2013

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    DOI： 10.5692/clinicalneurol.53.114

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  • Relapse of multiple sclerosis in a patient retaining CCR7-expressing T cells in CSF under fingolimod therapy Reviewed

    Akiko Yokoseki, Etsuji Saji, Musashi Arakawa, Mariko Hokari, Takanobu Ishiguro, Fumihiro Yanagimura, Tomohiko Ishihara, Kouichirou Okamoto, Masatoyo Nishizawa, Izumi Kawachi

    Multiple Sclerosis Journal   19 ( 9 )   1230 - 1233   2013

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    DOI： 10.1177/1352458513481395

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  • Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS Reviewed

    Atsushi Shiga, Tomohiko Ishihara, Akinori Miyashita, Misaki Kuwabara, Taisuke Kato, Norihiro Watanabe, Akie Yamahira, Chigusa Kondo, Akio Yokoseki, Masuhiro Takahashi, Ryozo Kuwano, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    PLoS ONE   7 ( 8 )   2012.8

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    DOI： 10.1371/journal.pone.0043120

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  • Clinical/Scientific notes Reviewed

    M. Omoto, S. Suzuki, T. Ikeuchi, T. Ishihara, T. Kobayashi, Y. Tsuboi, J. Ogasawara, M. Koga, M. Kawai, T. Iwaki, T. Kanda

    Neurology   78 ( 10 )   762 - 764   2012.3

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    DOI： 10.1212/WNL.0b013e318248e531

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  • Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia. Reviewed International journal

    Akio Yokoseki, Tomohiko Ishihara, Akihide Koyama, Atsushi Shiga, Mitsunori Yamada, Chieko Suzuki, Yoshiki Sekijima, Kyoko Maruta, Miyuki Tsuchiya, Hidetoshi Date, Tatsuya Sato, Masayoshi Tada, Takeshi Ikeuchi, Shoji Tsuji, Masatoyo Nishizawa, Osamu Onodera

    Brain : a journal of neurology   134 ( Pt 5 )   1387 - 99   2011.5

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    DOI： 10.1093/brain/awr069

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  • The phenotype spectrum of Japanese multiple system atrophy Reviewed

    Tetsutaro Ozawa, M. Tada, A. Kakita, O. Onodera, M. Tada, T. Ishihara, T. Morita, T. Shimohata, K. Wakabayashi, H. Takahashi, M. Nishizawa

    Journal of Neurology, Neurosurgery and Psychiatry   81 ( 11 )   1253 - 1255   2010.11

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    DOI： 10.1136/jnnp.2009.182576

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  • Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: A distinct clinicopathological and biochemical disease entity Reviewed

    Yong-Juan Fu, Yasushi Nishihira, Shigetoshi Kuroda, Yasuko Toyoshima, Tomohiko Ishihara, Makoto Shinozaki, Akinori Miyashita, Yue-Shan Piao, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Keisuke Iwanaga, Mitsuhiro Tsujihata, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa, Akiyoshi Kakita, Takeshi Ikeuchi, Hitoshi Takahashi

    Acta Neuropathologica   120 ( 1 )   21 - 32   2010.7

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    DOI： 10.1007/s00401-010-0649-2

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  • Sleep apnea associated with floppy epiglottis in adult-onset Alexander disease: A case report Reviewed

    Masanori Ishikawa, Takayoshi Shimohata, Tomohiko Ishihara, Hideaki Nakayama, Masahiko Tomita, Masatoyo Nishizawa

    Movement Disorders   25 ( 8 )   1098 - 1100   2010.6

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    DOI： 10.1002/mds.23042

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  • The clinical and pathological spectrum of TDP-43 associated ALS Reviewed

    Osamu Onodera, AMo Yokoseki, Chun-Feng Tan, Tomohiko Ishihara, Yasushi Nishiira, Yasuko Toyoshima, AMyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi

    Clinical Neurology   50 ( 11 )   940 - 942   2010

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    DOI： 10.5692/clinicalneurol.50.940

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  • FTLD/ALS as TDP-43 proteinopathies Reviewed

    Ishihara, T., Ariizumi, Y., Shiga, A., Yokoseki, A., Sato, T., Toyoshima, Y., Kakita, A., Takahashi, H., Nishizawa, M., Onodera, O.

    Clinical Neurology   50 ( 11 )   2010

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    DOI： 10.5692/clinicalneurol.50.1022

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  • The implications of TDP-43 mutations in pathogenesis of amyotrophic lateral sclerosis Reviewed

    Tomohiko Ishihara, Akio Yokoseki, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    Brain and Nerve   61 ( 11 )   1301 - 1307   2009.11

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  • Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation Reviewed

    Kensaku Kasuga, Tsukasa Ohno, Tomohiko Ishihara, Akinori Miyashita, Ryozo Kuwano, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    Journal of Neurology   256 ( 8 )   1351 - 1353   2009.8

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    DOI： 10.1007/s00415-009-5096-4

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  • Conflict of intentionsとびまん性脳梁病変を呈した50歳女性

    手塚 敏之, 下畑 享良, 石原 智彦, 大槻 美佳, 西澤 正豊

    臨床神経学   49 ( 1 )   57 - 57   2009.1

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  • 悪性腫瘍に合併した虚血性脳卒中の特徴

    高野 弘基, 赤岩 靖久, 新保 淳輔, 石原 智彦, 西澤 正豊

    臨床神経学   48 ( 12 )   1065 - 1065   2008.12

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  • 慢性腎臓病と脳内出血との関連についての検討

    赤岩 靖久, 石原 智彦, 新保 淳輔, 高野 弘基, 西澤 正豊

    臨床神経学   48 ( 12 )   1064 - 1064   2008.12

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  • Atypical Parkinsonism in distal myopathy with rimmed vacuoles Reviewed

    Tomohiko Ishihara, Tetsutaro Ozawa, Shuichi Igarashi, Yuko Kitsukawa, Masahito Takagi, Masaki Hirose, Takayoshi Tokutake, Keiko Tanaka, Masatoyo Nishizawa

    Movement Disorders   23 ( 6 )   912 - 915   2008.4

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    DOI： 10.1002/mds.22018

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  • Toxocara canis myelitis Reviewed

    Ishihara, T., Ozawa, T., Nemoto, M., Shinbo, J., Igarashi, S., Tanaka, K., Nishizawa, M.

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   96 ( 1 )   141 - 143   2007

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    DOI： 10.2169/naika.96.141

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  • Atypical micrographia associated with corticostriatal white matter lesions in systemic lupus erythematosus [2] Reviewed

    T. Ishihara, Tetsutaro Ozawa, M. Otsuki, J. Shimbo, K. Tanaka, M. Nishizawa

    Journal of Neurology, Neurosurgery and Psychiatry   77 ( 8 )   993 - 994   2006.8

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    DOI： 10.1136/jnnp.2005.083634

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  • New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2 Reviewed

    M. Takagi, T. Ozawa, K. Hara, S. Naruse, T. Ishihara, J. Shimbo, S. Igarashi, K. Tanaka, O. Onodera, M. Nishizawa

    Neurology   66 ( 8 )   1251 - 1252   2006.4

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    DOI： 10.1212/01.wnl.0000208415.90685.cd

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MISC

  • 孤発性ALSでのTDP-43病理の広がりとAPOE多型の関係

    畠野雄也, 畠野雄也, 石原智彦, 中原亜紗, 他田真理, 柿田明美, 小野寺理

    Dementia Japan   39 ( 4 )   2025

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  • Prognostic impact of cervical spine surgery in ALS

    OTSU Yutaka, OGINEZAWA Shinya, HATANO Yuya, ISHIHARA Tomohiko, WATANABE Kei, ONODERA Osamu

    日本神経学会学術大会プログラム・抄録集   66th   2025

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  • Hemorrhagic phenotype of cerebral small vessel disease associated with ABCC6 mutations

    KITAHARA Sho, ANDO Shoichiro, UEMURA Masahiro, HATANO Yuya, NOZAKI Hiroaki, ISHIHARA Tomohiko, ONODERA Osamu

    日本神経学会学術大会プログラム・抄録集   66th   2025

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  • Determining the pathological thresholds for CAG repeat units in CACNA1A

    HATANO Yuya, HATANO Yuya, ISHIHARA Tomohiko, HIROKAWA Sachiko, DATE Hidetoshi, TAKAHASHI Yuji, MIZUSAWA Hidehiro, ONODERA Osamu

    日本神経学会学術大会プログラム・抄録集   66th   2025

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  • 研究手法 MOVA:AlphaFold2によるミスセンスバリアントの効果予測

    畠野雄也, 畠野雄也, 石原智彦, 小野寺理

    遺伝子医学   14 ( 1 )   2024

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  • TDP-43のマウス運動神経回路内における病態伝播の機序

    坪口晋太朗, 中村由香, 石原智彦, 加藤泰介, 佐藤時春, 小山哲秀, 森秀樹, 小池佑佳, 小野寺理, 小野寺理, 上野将紀

    日本生物学的精神医学会(Web)   46th   2024

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  • TDP-43 differentially propagates to induce degeneration in the motor circuit

    坪口晋太朗, 中村由香, 石原智彦, 加藤泰介, 佐藤時春, 小山哲秀, 森秀樹, 小池佑佳, 小野寺理, 小野寺理, 上野将紀

    Dementia Japan   37 ( 4 )   2023

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  • MOVA: A method of missense variant pathogenicity using AlphaFold2

    ISHIHARA Tomohiko, HATANO Yuya, ONODERA Osamu

    日本人類遺伝学会大会(CD-ROM)   68th   2023

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  • 運動失調症の医療水準,患者QOLの向上に資する研究班 1)ポリグルタミン病に対する蛋白質凝集阻害薬の第II相試験 2)機械学習法を用いたポリグルタミン病発症予測

    小野寺理, 畠野雄也, 石原智彦

    運動失調症の医療水準、患者QOLの向上に資する研究班 令和4年度 総括・分担研究報告書(Web)   2023

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  • 新規遺伝子多型病原性予測法MOVAのEOAD原因遺伝子への適応

    畠野雄也, 小野寺理, 石原智彦

    Dementia Japan   36 ( 4 )   2022

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  • 加齢と関連したDNA脱メチル化がTDP-43量の自己調節機構を障害する

    小池佑佳, 須貝章弘, 原範和, 伊藤絢子, 横関明男, 石原智彦, 山岸拓磨, 坪口晋太朗, 他田真理, 池内健, 柿田明美, 小野寺理

    Dementia Japan   35 ( 4 )   2021

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  • The association of early onset severe cerebral small vessel disease and APOE

    HATANO Yuya, ISHIHARA Tomohiko, UEMURA Masahiro, ONODERA Osamu

    日本神経学会学術大会プログラム・抄録集   62nd   2021

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  • Clinicopathologic study of two patients with amyotrophic lateral sclerosis harboring TBK1 mutations

    TADA Mari, HATANO Yuya, TAKESHIMA Akari, SAITO Rie, SAJI Etsuji, TOKUTAKE Takayoshi, ISHIHARA Tomohiko, TOYOSHIMA Yasuko, ONODERA Osamu, KAKITA Akiyoshi

    日本神経学会学術大会プログラム・抄録集   62nd   2021

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  • 神経変性疾患領域の基盤的調査研究 孤発性ALSにおける認知症発症リスクとしてのAPOE2

    小野寺理, 畠野雄也, 石原智彦, 他田真理, 柿田明美

    神経変性疾患領域の基盤的調査研究 令和2年度 総括・分担研究報告書(Web)   2021

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  • 運動失調の医療水準,患者QOLの向上に資する研究班 DRPLAとMJD,SCA6の発症年齢とCAGリピート数の分布の比較

    小野寺理, 畠野雄也, 石原智彦, 廣川祥子

    運動失調症の医療水準,患者QOLの向上に資する研究班 令和2年度 総括・分担研究報告書(Web)   2021

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  • Transactive response DNA-binding protein 43kDa(TDP-43)凝集体の形成と分解からみたamyotrophic lateral sclerosis(ALS)の分子機構

    笠原 壮, 石原 智彦, 小池 佑佳, 須貝 章弘, 小野寺 理

    臨床神経学   60 ( 2 )   109 - 116   2020.2

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  • Spreading of TDP-43 via direct corticospinal connections in mouse models

    TSUBOGUCHI Shintaro, NAKAMURA Yuka, ISHIHARA Tomohiko, KATO Taisuke, KOYAMA Akihide, SATO Tokiharu, YOSHIDA Yutaka, UENO Masaki, ONODERA Osamu

    日本神経学会学術大会プログラム・抄録集   61st   2020

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  • 脊髄小脳変性症・多系統萎縮症について[第2部]脊髄小脳変性症の治療の現状と展望

    大津裕, 今野卓哉, 石原智彦, 小野寺理

    月刊難病と在宅ケア   26 ( 8 )   2020

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  • 一過性感覚障害とくも膜下出血を繰り返し,TTR遺伝子Y69H変異が判明した,Oculoleptomeningeal amyloidosisの58歳女性例

    黒羽泰子, 畠野雄也, 石原智彦, 長谷川有香, 高橋哲哉, 松原奈絵, 小池亮子

    臨床神経学(Web)   60 ( 5 )   2020

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  • 【ジストニア診療のupdate】ジストニア 遺伝子診断からのアプローチ

    加藤 怜, 石原 智彦, 小野寺 理

    脳神経内科   91 ( 6 )   727 - 738   2019.12

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  • 【ALS 2019】TDP-43封入体から解くALSの分子病態

    坪口 晋太朗, 石原 智彦, 須貝 章弘, 横関 明男, 小野寺 理

    BRAIN and NERVE: 神経研究の進歩   71 ( 11 )   1183 - 1189   2019.11

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  • 【非翻訳領域の繰り返し配列伸長変異による神経疾患の臨床および病態機序】脆弱X症候群および脆弱X関連振戦/運動失調症候群の臨床

    畠野 雄也, 石原 智彦, 小野寺 理

    脳神経内科   91 ( 4 )   443 - 450   2019.10

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  • 【細胞内の相分離 タンパク質や核酸分子を整理し、反応の場を作り、生命を駆動する】ALS病態における液-液相分離と非膜性構造の異常

    小池 佑佳, 石原 智彦, 小野寺 理

    実験医学   37 ( 9 )   1416 - 1420   2019.6

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  • 【神経疾患とトレース・メタル-知っていますか?】鉄 Friedreich失調症と鉄代謝

    坪口 晋太朗, 石原 智彦, 小野寺 理

    Clinical Neuroscience   37 ( 3 )   308 - 310   2019.3

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  • 臨床経過および画像所見よりMSA-Pとの鑑別を要したPARK8の一例

    石原 智彦, 林 秀樹, 齋藤 奈つみ, 安藤 昭一朗, 小野寺 理

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   12回   100 - 100   2018.7

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    Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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  • 血液透析療法下で、脳出血発症後に脳浮腫が急速進行した58歳女性例

    大津 裕, 金山 武史, 二宮 格, 石原 智彦, 保坂 聖子, 忰田 亮平, 成田 一衛, 小野寺 理

    臨床神経学   58 ( 1 )   55 - 55   2018.1

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  • 有痛性筋痙攣に対して免疫グロブリン静注療法が有効であった筋萎縮性側索硬化症の1例

    茂木 崇秀, 石原 智彦, 他田 正義, 河内 泉, 下畑 享良, 小野寺 理

    神経治療学   34 ( 6 )   S199 - S199   2017.11

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  • 下垂体腫瘍摘出術後に発症した橋中心及び橋外性髄鞘崩壊症の1例

    石黒敬信, 石原智彦, 畠野雄也, 阿部孝洋, 下畑享良, 西澤正豊

    臨床神経学(Web)   57 ( 1 )   2017

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  • 3か月の経過で両側性の視神経障害を来たした63歳男性

    畠野雄也, 石原智彦, 坪口晋太朗, 矢野隆二, 植木智志, 畑瀬哲尚, 下畑享良, 西澤正豊

    臨床神経学(Web)   56 ( 2 )   2016

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  • ALSにおけるGEM小体とU snRNA異常 RNA代謝異常は運動神経変性の共通した病態機序となるか

    小池 佑佳, 石原 智彦, 西澤 正豊, 小野寺 理

    神経内科   83 ( 2 )   175 - 184   2015.8

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    機能性RNAの中の代表的なものに、転移RNA、リボソームRNAなどがある。これらは、それぞれ翻訳において重要な役割を有する。この機能性RNAの一種にuridine rich small nuclear RNA(UsnRNA)がある。細胞内のmRNAや機能性RNAの量的、質的な多様性、恒常性のことをribostasisと称し、筋萎縮性側索硬化症(ALS)の病態機序との関連が注目されている。RNA代謝の中で、UsnRNAおよびUsnRNAの成熟に関わる核内の構造物であるGemini of coiled bodyとALSとの関連について最新の知見を述べた。

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  • 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 ALSではいつ細胞障害が始まるのか?TDP-43陽性封入体との関係

    小野寺理, 須貝章弘, 小山哲秀, 加藤泰介, 志賀篤, 今野卓哉, 小山美咲, 石原智彦, 西澤正豊

    異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 平成26年度 総括・分担研究報告書   2015

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  • TDP-43の新展開 ALSにおけるspliceosome異常

    石原 智彦, 柿田 明美, 高橋 均, 小野寺 理, 西澤 正豊

    臨床神経学   54 ( 12 )   1155 - 1157   2014.12

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  • 12 原発性胆汁性肝硬変の経過中に筋炎・II型呼吸不全・不整脈を呈した1例（一般演題, 第54回下越内科集談会）

    128 ( 6 )   281 - 281   2014.6

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  • 【神経症候群(第2版)-その他の神経疾患を含めて-】変性疾患 運動ニューロン疾患 筋萎縮性側索硬化症 遺伝性ALS ALS10(TARDBP遺伝子変異によるALS)

    酒井 直子, 石原 智彦, 小野寺 理, 西澤 正豊

    日本臨床   別冊 ( 神経症候群II )   491 - 495   2014.3

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  • 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 TDP-43量は自己mRNAのpolyA選択,スプライシング,核貯留の協働により制御される

    須貝章弘, 小山哲秀, 加藤泰介, 志賀篤, 今野卓哉, 小山美咲, 石原智彦, 西澤正豊, 小野寺理

    異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 平成25年度 総括・分担研究報告書   2014

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  • 神経変性疾患に関する調査研究 TDP-43 mRNAのポリA選択とスプライシングを介した自己蛋白量の制御機構

    小野寺理, 須貝章弘, 小山哲秀, 加藤泰介, 志賀篤, 今野卓哉, 小山美咲, 石原智彦, 西澤正豊

    神経変性疾患に関する調査研究 平成25年度 総括・分担研究報告書   2014

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  • 2 抗NMDA受容体脳炎後の情動不安定, 被刺激性亢進に高用量クエチアピンが有効であったと考えられる1症例（Ⅰ．一般演題, 第15回新潟GHP研究会）

    菊地 佑, 鈴木 雄太郎, 大竹 将貴, 福井 直樹, 大塚 道人, 石原 智彦, 染矢 俊幸

    新潟医学会雑誌   127 ( 12 )   697 - 698   2013.12

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  • 筋萎縮性側索硬化症におけるGemini of coiled bodyの減少

    有泉 優子, 石原 智彦, 横関 明男, 譚 春鳳, 三木 ゆかり, 柿田 明美, 高橋 均, 西澤 正豊, 小野寺 理

    臨床神経学   53 ( 12 )   1497 - 1497   2013.12

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  • 腫瘍摘出術及びステロイド治療後も残存した情動不安定及び被刺激性亢進に高用量quetiapineが有効であった抗NMDA受容体脳炎の1症例

    菊地 佑, 鈴木 雄太郎, 大竹 将貴, 福井 直樹, 大塚 道人, 石原 智彦, 染矢 俊幸

    日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集   23回・43回   210 - 210   2013.10

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    Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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  • 9 心機能障害を合併した抗ミトコンドリア抗体陽性筋炎の51歳男性例(一般演題, 第53回下越内科集談会)

    笠見 卓哉, 石原 智彦, 柳村 文寛, 穂苅 万李子, 河内 泉, 下畑 享良, 西澤 正豊

    新潟医学会雑誌   127 ( 7 )   388 - 389   2013.7

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    Other Link： http://search.jamas.or.jp/link/ui/2014076253

  • 筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 TDP-43 mRNAの制御機構

    小野寺理, 小山哲秀, 須貝章弘, 今野卓哉, 小山美咲, 石原智彦, 西澤正豊

    筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 平成22-24年度 総合研究報告書   2013

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  • 筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 TDP-43 mRNAの制御機構

    小野寺理, 小山哲秀, 須貝章弘, 今野卓哉, 小山美咲, 石原智彦, 西澤正豊

    筋萎縮性側索硬化症の分子病態解明と新規治療法創出に関する研究 平成24年度 総括・分担研究報告書   2013

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  • ALS患者神経組織ではスプライシング関連機能性RNAが低下する

    石原 智彦, 志賀 篤, 横尾 麻衣子, 有泉 優子, 横関 明男, 譚 春鳳, 柿田 明美, 西澤 正豊, 高橋 均, 小野寺 理

    臨床神経学   52 ( 12 )   1409 - 1409   2012.12

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  • 【わが国の遺伝性ALS】ALS10(TARDBP遺伝子変異によるALS)

    横関 明男, 石原 智彦, 今野 卓哉, 西澤 正豊, 小野寺 理

    神経内科   76 ( 5 )   489 - 496   2012.5

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  • 神経変性疾患に関する調査研究 RNA代謝異常の観点から TDP-43の自己調節機能の観点からのALSの病態機序の考察

    小野寺理, 横関明男, 有泉優子, 佐藤達哉, 近藤千草, 石原智彦, 桑原美咲, 今野拓也, 加藤泰介, 西澤正豊, 小山哲秀, 志賀篤, 譚春風, 豊島靖子, 高橋均, 廣川祥子, 佐藤俊哉, 横山峰介

    神経変性疾患に関する調査研究 平成23年度 総括・分担研究報告書   2012

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  • TDP-43の選択的スプライシングを介した自己発現調節

    石原 智彦, 桑原 美咲, 志賀 篤, 藤野 赳至, 近藤 千草, 西澤 正豊, 小野寺 理

    臨床神経学   51 ( 12 )   1273 - 1273   2011.12

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  • 筋萎縮性側索硬化症におけるsmall nuclear RNAsの減少

    石原 智彦

    新潟医学会雑誌   125 ( 9 )   469 - 481   2011.9

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  • 【ALS-臨床と分子病態研究の進歩】家族性ALS ALS10(遺伝性ALS-TDP)の臨床と病理

    今野 卓哉, 石原 智彦, 西澤 正豊, 小野寺 理

    Clinical Neuroscience   29 ( 9 )   1019 - 1021   2011.9

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  • 【Parkinson病の新しい問題点】Parkinson病のcamptocormiaと首下がり

    石原 智彦, 下畑 享良, 西澤 正豊

    神経内科   74 ( 1 )   64 - 67   2011.1

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  • ALS関連蛋白TDP-43の自己発現調節機能に関与するスプライシング因子の検討

    桑原美咲, 石原智彦, 志賀篤, 今野卓哉, 小山哲秀, 西澤正豊, 小野寺理

    日本分子生物学会年会プログラム・要旨集(Web)   34th   2011

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  • 筋萎縮性側索硬化症におけるsnRNAの変化(Alteration of snRNAs in amyotrophic lateral sclerosis)

    石原 智彦, 志賀 篤, 柿田 明美, 横関 明男, 西澤 正豊, 高橋 均, 小野寺 理

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   2P - 0917   2010.12

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  • 低アルブミン血症と眼球運動失行を伴う早発型失調症39家系の臨床遺伝学的検討

    横関 明男, 石原 智彦, 山田 光則, 伊達 英俊, 辻 省次, 小野寺 理, 西澤 正豊

    臨床神経学   50 ( 12 )   1081 - 1081   2010.12

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  • TDP-43のリン酸化による細胞内局在、凝集体形成の検討

    有泉 優子, 横尾 麻理子, 志賀 篤, 石原 智彦, 横関 明男, 小野寺 理, 西澤 正豊

    臨床神経学   50 ( 12 )   1199 - 1199   2010.12

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  • TDP-43と核内小体の構成蛋白との蛋白間相互作用の検討

    佐藤 達哉, 横尾 麻理子, 有泉 優子, 石原 智彦, 小野寺 理, 西澤 正豊

    臨床神経学   50 ( 12 )   1199 - 1199   2010.12

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  • TDP-43の喪失により、細胞内膜系関連遺伝子のスプライシング異常が起こる(TDP-43 depletion causes aberrant splicing in the genes associated with endomembrane system)

    志賀 篤, 石原 智彦, 宮下 哲典, 横尾 麻理子, 有泉 優子, 横関 明男, 桑野 良三, 西澤 正豊, 小野寺 理

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   2P - 0916   2010.12

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    Language：English   Publisher：(公社)日本生化学会  

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  • 筋萎縮性側索硬化症の病因TDP-43およびFUS/TLS研究の最前線 TDP-43/ALSの臨床と病理

    小野寺 理, 横関 明男, 譚 春鳳, 石原 智彦, 西平 靖, 豊島 靖子, 柿田 明美, 西澤 正豊, 高橋 均

    臨床神経学   50 ( 11 )   940 - 942   2010.11

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  • 認知症研究の新しい視点 TDP-43プロテイノパチーとしてのFTLD/ALS

    石原 智彦, 有泉 優子, 志賀 篤, 横関 明男, 佐藤 達哉, 豊島 靖子, 柿田 明美, 高橋 均, 西澤 正豊, 小野寺 理

    臨床神経学   50 ( 11 )   1022 - 1024   2010.11

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  • 【神経変性疾患におけるTDP-43】家族性筋萎縮性側索硬化症とTDP-43

    石原 智彦, 横関 明男, 西澤 正豊, 高橋 均, 小野寺 理

    最新医学   65 ( 7 )   1648 - 1653   2010.7

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    Language：Japanese   Publisher：(株)最新医学社  

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  • Cytoplasmic C-Terminus TDP-43 Aggregate Leads to Increased Phosphorylation of Full-Length TDP-43 in Culture Cell

    Yuko Ariizumi, Tomohiko Ishihara, Mariko Yokoo, Atsushi Shiga, Akio Yokoseki, Osamu Onodera, Masatoyo Nishizawa

    NEUROLOGY   74 ( 9 )   A502 - A502   2010.3

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    Language：English   Publishing type：Research paper, summary (international conference)  

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  • ALS関連変異型TDP-43の機能と細胞毒性の検討

    横関 明男, 志賀 篤, 小池 佑佳, 石原 智彦, 有泉 優子, 横尾 麻理子, 小野寺 理, 西澤 正豊

    臨床神経学   49 ( 12 )   1055 - 1055   2009.12

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  • 遺伝子変異を伴った家族性アルツハイマー病の表現型の比較

    池内 健, 春日 健作, 野崎 洋明, 石原 智彦, 金子 博之, 篠崎 真, 桑野 良三, 小野寺 理, 西澤 正豊

    臨床神経学   49 ( 12 )   984 - 984   2009.12

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  • ALS関連変異型TDP43の細胞内動態の検討

    有泉 優子, 志賀 篤, 石原 智彦, 横尾 麻理子, 横関 明男, 小野寺 理, 西澤 正豊

    臨床神経学   49 ( 12 )   1027 - 1027   2009.12

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  • 【前頭側頭葉変性症】TDP-43の遺伝子変異とその意義

    石原 智彦, 横関 明男, 西澤 正豊, 高橋 均, 小野寺 理

    BRAIN and NERVE: 神経研究の進歩   61 ( 11 )   1301 - 1307   2009.11

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    Language：Japanese   Publisher：(株)医学書院  

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  • 慢性腎臓病と脳卒中病型との関連

    高野 弘基, 赤岩 靖久, 石原 智彦, 新保 淳輔, 西澤 正豊

    脳卒中   30 ( 2 )   317 - 317   2008.3

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  • ADEM 病初期にMRI異常を呈さない重症急性散在性脳脊髄炎の検討

    徳永 純, 河内 泉, 柳川 香織, 野村 俊春, 石川 正典, 石原 智彦, 田中 惠子, 西澤 正豊

    NEUROINFECTION   12 ( 2 )   195 - 195   2007.9

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    Language：Japanese   Publisher：日本神経感染症学会  

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  • 結核性髄膜炎との鑑別に苦慮した神経サルコイドーシスの1例

    石原 智彦, 小澤 鉄太郎, 高木 正仁, 横関 明男, 大崎 暁彦, 高野 明人, 五十嵐 修一, 田中 恵子, 西澤 正豊

    新潟医学会雑誌   119 ( 4 )   271 - 271   2005.4

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Research Projects

  • AIと剖検組織を用いたALSの新規原因遺伝子同定

    Grant number：24K10506

    2024.4 - 2027.3

    System name：科学研究費助成事業

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    石原 智彦, 畠野 雄也, 他田 真理

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • ALSのTDP-43病理多型を規定する遺伝的因子の探索

    Grant number：21K07272

    2021.4 - 2024.3

    System name：科学研究費助成事業 基盤研究(C)

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    石原 智彦, 他田 真理

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    本研究は神経変性疾患のALS（筋萎縮性側索硬化症: amyotrophic lateral sclerosis）剖検例での網羅的遺伝子解析（エクソーム解析）を主たる目的としている。ALSにおける遺伝子変異の解析は、その病態生理の理解、予後評価、治療法開発に貢献しうる。
    2021年度には8検体由来の病理検体から抽出したDNAを用いて新規エクソーム解析を実施し、既存のALS原因40遺伝子の変異について検討した。ミスセンス、ナンセンス、スプライシング変異などの変異の種類、データベース上の変異頻度に基づく解析では、有意な変異を認めなかった。
    また新規遺伝子候補を検索するため、テキストマイニングとPubmed データベースでの抄録を用いた解析を実施した。2000年~2019年までの163948論文を対象に、RNA binding protein 1164遺伝子について既知のALS原因遺伝子とのベクトルの類似性を検討し、複数の候補遺伝子を見出した。さら候補遺伝子由来の蛋白質について、既知のALS原因遺伝子との類似性を評価した。評価項目には天然変性領域、プリオンドメイン構造の割合を用いた。その結果、テキストマイニング評価で見出された候補遺伝子は、統計学的に有意にこれらの特徴を持つことを確認した。当施設保有のALS剖検例のうち、既知の遺伝子変異保有例を除外した108例のエクソームデータを確認したところ、8/108例（7.4%）で候補遺伝子変異を見出した。引き続きこれら遺伝子変異の病態意義の解析を進める予定である。

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  • The disease mechanism and biomarker of ALS, the view from TDP-43 alternative splicing

    Grant number：17K09750

    2017.4 - 2020.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    Ishihara Tomohiko

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    We carried out TDP-43 mRNA alternative splicing (AS) analysis to elucidate the pathomechanism of amyotrophic lateral sclerosis (ALS). TDP-43 is a major component of inclusion body in ALS and is a key molecule of this disease. We found a unique TDP-43 mRNA AS pattern in neural tissue from ALS autopsied cases. Furthermore, the protein derived from the AS mRNA showed easy aggregation property. The same AS pattern was also found in the cerebellum, which is a non-injured tissue of ALS, but no difference was found in the blood cell mRNA from the control group, and it was not established as a biomarker.

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  • Therapeutic strategy for ALS with nucleic acid technology focusing on the vulnerability of TDP-43 autoregulation

    Grant number：17K09751

    2017.4 - 2020.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    Sugai Akihiro

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    In amyotrophic lateral sclerosis (ALS), the nuclear protein TDP-43 accumulates in the cytoplasm. TDP-43 binds to its pre-mRNA, induces alternative splicing, and autoregulates its expression levels. Here, we first constructed a mathematical model and predicted that transcriptional redundancy that underpins TDP-43 autoregulation could drive TDP-43 pathology. Then, we used an antisense oligo to suppress TDP-43 alternative splicing and manifested transcriptional redundancy. As a result, in the mouse spinal cord, the increase and fragmentation of insoluble TDP-43 and decrease in the number of motor neurons were observed. These results, which recapitulate part of the ALS pathology, suggested that this alternative splicing could be a promising therapeutic target for ALS.

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  • Elucidation of a mechanism of ALS system selectivity focusing on TDP-43 function in interneurons.

    Grant number：15K19479

    2015.4 - 2017.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Research category：Grant-in-Aid for Young Scientists (B)

    Awarding organization：Japan Society for the Promotion of Science

    Ishihara Tomohiko

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    Grant amount：\3510000 （ Direct Cost: \2700000 、 Indirect Cost：\810000 ）

    We aimed to elucidate the mechanism of the pathogenesis of amyotrophic lateral sclerosis (ALS). We have already reported the decrease of the main component of splicing machinery, U snRNAs and GEM bodies, and several aberrant splicing in ALS affected tissues.
    In this study, we intended to clarify the role of interneurons in ALS and its RNA metabolism disorder. We found that it is necessary to pay attention to RNA fragmentation in the isolation and quantification of mRNA from formalin-fixed paraffin-embedded tissue. Furthermore, we focused on stasimon mRNA splicing which was reported as a cause of motor neuron degeneration mediated by interneurons disability in spinal muscular atrophy model animals, and confirmed the same splicing mutation in TDP-43 expression suppressing cells.

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  • Autoreguation of TDP-43 in ALS

    Grant number：25253065

    2013.4 - 2016.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Research category：Grant-in-Aid for Scientific Research (A)

    Awarding organization：Japan Society for the Promotion of Science

    Nishizawa Masatoyo, ONODERA Osamu, ISHIHARA Tomohiko, KAKITA Akiyoshi, SATO Toshiya

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    Grant amount：\45890000 （ Direct Cost: \35300000 、 Indirect Cost：\10590000 ）

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. We show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons; especially neurons with mislocalized TDP-43; the amount of TARDBP mRNA is increased in the cytoplasm. Our observations suggests that that the absence of nuclear TDP-43 induces an abnormal autoregulation.

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  • The pathogenesis of GEM bodies reduction in ALS affected tissues.

    Grant number：25860703

    2013.4 - 2015.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Research category：Grant-in-Aid for Young Scientists (B)

    Awarding organization：Japan Society for the Promotion of Science

    ISHIHARA Tomohiko

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    Grant amount：\3640000 （ Direct Cost: \2800000 、 Indirect Cost：\840000 ）

    Our object is the elucidation of ALS pathogenesis. We have already found the reduction of minor spliceosomal U snRNA and GEM bodies in ALS affected tissues. U snRNA is main component of the splicing machinery and GEM bodies have important role in the maturation of U snRNAs. We intended to clarify the pathogenesis of GEM bodies reduction and aberrant splicing in ALS affected tissues. In this study, we found the reduction of SMN mRNA in TDP-43 depleted cells. SMN protein is main component of GME bodies. And there were minor spliceosome dependent splicing aberrations in ALS affected tissues.

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  • Alteration of snRNAs in amyotrophic lateral sclerosis

    Grant number：23890060

    2011 - 2012

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity start-up

    Research category：Grant-in-Aid for Research Activity start-up

    Awarding organization：Japan Society for the Promotion of Science

    ISHIHARA Tomohiko

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    Grant amount：\3250000 （ Direct Cost: \2500000 、 Indirect Cost：\750000 ）

    We stated and investigated the hypothesis that the dysfunction of TDP-43 causesreduction of snRNAs in amyotrophic lateral sclerosis (ALS). We revealed thedownregulation of U12 snRNA in the tissues affected with ALS and not in non-affectedtissues. Several U12-type intron splicing tended to be downregulated in ALS affectedtissues and culture cells with depleted TDP-43.

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